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PubMed2004

First pharmacophoric hypothesis for T-type calcium channel blockers.

A three-dimensional pharmacophore model was developed for T-type calcium channel blockers in order to map common structural features of highly active compounds by using CATALYST program. In the absence of three dimensional structure based information like binding mode and unavailability of more number of specific T-type calcium channel blockers, this hypothesis which consists of three hydrophobic regions, one hydrogen bond acceptor and one positive ionizable regions will act as a valuable tool in designing new ligands. Further more after the withdrawal of mibefradil, the first marketed T-type calcium channel blocker, due to the drug-drug interactions, there is an urgent need for more work in this interest.

Calcium Channel Blockers↗
PubMed1990

The use of calcium channel blockers in obstetrics and gynecology; a review.

Since their introduction, calcium channel blockers gained wide use in the treatment in various fields of medicine. Calcium channel blockers were shown to inhibit contractions of the pregnant and nonpregnant uterus, and lately their properties have made it, theoretically, an ideal candidate for the use in severe pregnancy-induced hypertension: it is effective in lowering blood pressure, has a fast and long-standing action, may be conveniently administered via the oral route, and it is not associated with serious side effects.

Animals↗
PubMedDate not supplied

Solution synthesis of calciseptine, an L-type specific calcium channel blocker.

Calciseptine, an L-type specific calcium channel blocker consisting of 60 amino acid residues with four intramolecular disulfide bonds, was synthesized by the solution procedure applying our maximum protection strategy. The recently developed solvent systems used were a mixture of chloroform or dichloromethane and trifluoroethanol; they were useful for the synthesis of slightly soluble protected peptides. After removal of all the protecting groups by our two-step HF procedure followed by treatment with mercuric acetate, the peptide was folded into its native form by air oxidation, in which redox reagents were necessary to accelerate the correct disulfide bond formation. The product was purified to homogeneity and found to block contractions of the rat thoracic aorta induced by 40 mM K+ with the same potency as that of the natural product. In addition, this peptide was found to block contractions of various rat smooth muscle preparations as well as increase in cytosolic free calcium concentration induced by a high concentration of extracellular K+.

Amino Acid Sequence↗
PubMed1995

Effects of calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in porcine ciliary arteries.

Calcium channel blockers are increasingly used in ophthalmology, for instance in patients with visual field defects caused by vasospasm. Endothelin is a new vasoactive peptide which also has been implicated in hypoperfusion of the ophthalmic circulation. This study investigated the effects of the calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in isolated porcine ciliary arteries (diameter 200-250 microns). Isolated porcine ciliary arteries were suspended in myograph systems filled with modified Krebs-Ringer solution (37 degrees C; 95% O2/5% CO2) for isometric tension recording. Endothelin-1 (10(-12) -10(-7) M) induced potent concentration-dependent contractions of porcine ciliary arteries (PD50 = 8.3 +/- 0.1; n = 7). Lacidipine (10(-5) -10(-7) M) and nifedipine (10(-5) M) significantly reduced the contractions and decreased the sensitivity to endothelin-1 as compared to control (P < 0.03). On the other hand, endothelium-dependent relaxations to bradykinin (10(-10) -10(-6) M) and endothelium-independent relaxations to sodium nitroprusside (10(-10) -10(-4) M) remained unaffected by the calcium channel blocker. These findings demonstrate that in porcine ciliary arteries, the calcium channel blockers selectively inhibit endothelin-1-induced contractions, while leaving endothelium-dependent and endothelium-independent relaxations unaffected. This property of calcium channel blockers may contribute to the clinical efficacy of this class of drugs in patients with ocular vasospasms.

Animals↗
PubMedDate not supplied

Screening procedure for detection of dihydropyridine calcium channel blocker metabolites in urine as part of a systematic toxicological analysis procedure for acidic compounds by gas chromatography-mass spectrometry after extractive methylation.

A gas chromatographic-mass spectrometric (GC-MS) screening procedure was developed for the detection of dihydropyridine calcium channel blocker ("calcium antagonist") metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons after extractive methylation. The part of the phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by capillary GC and identified by computerized MS in the full scan mode. Using mass chromatography with the ions m/z 139, 284, 297, 298, 310, 312, 313, 318, 324, and 332, the possible presence of calcium channel blocker metabolites could be indicated. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with the reference spectra recorded during this study. This method allowed the detection of therapeutic concentrations of amlodipine, felodipine, isradipine, nifedipine, nilvadipine, nimodipine, nisoldipine, and nitrendipine in human urine samples. Because urine samples from patients treated with nicardipine were not available, the detection of nicardipine in rat urine was studied. The overall recovery ranged between 67 and 77% with a coefficient of variation of less than 10%, and the limit of detection was at least 10 ng/mL (signal-to-noise ratio = 3) in the full-scan mode.

Acids↗
PubMed1994

Delay of experimentally induced preterm labour in rats with calcium channel blockers and salbutamol.

The effect of some calcium channel blockers on spontaneous activity of uterine strips obtained from 16 day pregnant rats was observed and compared with salbutamol. Nifedipine (2.9, 14 nM), verapamil (2, 10 nM) and diltiazem (11,22nM) both at low and high doses significantly abolished spontaneous contractions which was gradual and persistent. However, salbutamol (4.2, 21 nM) abolished spontaneous activity immediately but the response was shortlived. The effect of these agents was also investigated on experimentally induced preterm labour in rats (ovariectomized on day 16 of pregnancy). In the control group only 21% of foetuses were retained at the end of 48 hr. Nifedipine, verapamil, diltiazem and salbutamol administered ip 8 hourly protected 91%, 90%, 78% and 61% of foetuses from delivery at 48 hr respectively. The rank order of efficacy was nifedipine > verapamil > diltiazem > salbutamol.

Albuterol↗
PubMed1989

Calcium channel blockers in acute myocardial infarction and unstable angina: an overview.

OBJECTIVE: To assess the effects of calcium channel blockers on development of infarcts, reinfarction, and mortality. DESIGN: A systematic overview of all randomised trials of calcium channel blockers in myocardial infarction and unstable angina. PATIENTS: 19,000 Patients in 28 randomised trials. RESULTS: In the trials of myocardial infarction 873 deaths occurred among 8870 patients randomised to active treatment compared with 825 deaths among 8889 control patients (odds ratio of 1.06, 95% confidence interval of 0.96 to 1.18). There was no evidence of a beneficial effect on development and size of infarcts or rate of reinfarction. The results were similar in short term trials in which treatment was confined to the acute phase and those in which treatment was started some weeks later and continued for a year or two. There was no evidence of heterogeneity among different calcium channel blockers in their effects on any end point. The results were similar in the unstable angina trials (110 out of 561 patients treated with calcium channel blocker compared with 104 out of 548 controls developed a myocardial infarction; 14 out of 591 treated compared with nine out of 578 controls died). CONCLUSIONS: Calcium channel blockers do not reduce the risk of initial or recurrent infarction or death when given routinely to patients with acute myocardial infarction or unstable angina.

Acute Disease↗
PubMed1997

Inhibition of [3H]-U69593 binding and the cardiac effects of U50, 488H by calcium channel blockers in the rat heart.

1. The calcium channel blockers (CCBs), nifedipine, nicardipine, diltiazem and verapamil, were used to displace the binding of [3H]-U69593 ((5a, 7a,8b)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5] dec-8-yl)-benzeneacetamide), a specific kappa-opioid agonist, in the rat cardiac sarcolemma. The CCBs competed with the binding of [3H]-U69593 (4 nM) in a dose-dependent manner. The displacing potency of verapamil was 55 times greater than that of nifedipine. 2. The effects of two CCBs, verapamil and nifedipine, on the arrhythmogenic action of kappa-receptor stimulation by a specific kappa-receptor agonist, U50,488H (trans-(+/-(-3),4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeacetamide methanesulphonate), were also studied in the rat isolated perfused heart. U50,488H 80-800 nmol dose-dependently induced arrhythmias, which were completely abolished by a selective kappa-receptor antagonist, nor-BNI (nor-binaltorphimine, 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan -3,4',14, 14'-tetrol), at 100 nmol. The arrhythmogenic effect was also attenuated by both verapamil and nifedipine in a dose-dependent manner. The ED50 values for verapamil and nifedipine were 2.75 and 63.7 nmol, respectively. The antiarrhythmic potencies of these two CCBs were correlated to their displacing potencies and inversely related to their well known potencies in inhibiting transmembrane Ca2+ influx in the cardiac muscle. 3. Measurement of [Ca2+]i in the absence of free extracellular Ca2+ by a spectrofluorometric method, with fura-2 as Ca2+ indicator, showed that U50,488H 5 x 10(-5) M slowly increased [Ca2+]i in single ventricular myocytes and this effect was abolished by pretreatment with nor-BNI (5 microM), or ryanodine (5 microM). Verapamil 1 and 10 microM abolished the effect of U50,488H in 37.5% (3 out of 8) and 100% (12 out of 12) of the cells studied, respectively. On the other hand, nifedipine 10 and 100 microM had no effect at all. Neither verapamil nor nifedipine exerted any significant effect on the caffeine-induced Ca2+ transient. 4. The observations suggest that CCBs may inhibit the actions of kappa-receptor stimulation at the level of the kappa-receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMedDate not supplied

Calcium-channel blockers in acute myocardial infarction.

The calcium-channel blockers are useful in treating a variety of cardiovascular disorders. Due to their antiischemic and spasmolytic properties, these agents have been studied in the prophylaxis and treatment of acute myocardial infarction. This article reviews this application with respect to reduction of mortality, infarct size, and reinfarction rate. Of the agents currently available for clinical use, nifedipine has been studied most extensively. This agent shows no beneficial effects in this setting and its use may in fact be harmful. Of the few trials that have been conducted with verapamil, none have shown decreased mortality. Verapamil may reduce infarct size although further confirmation is required. Diltiazem is the only agent that has been shown to have short- and long-term benefits in the patient with acute myocardial infarction. Proper patient selection is of utmost importance in ensuring successful therapy. In particular, those patients with non-Q-wave infarctions and/or normal left ventricular function can be expected to derive the most benefit in terms of reducing mortality and reinfarction rate associated with the acute event.

Calcium Channel Blockers↗
PubMed1994

Role of renal dopamine D1 receptors in natriuresis induced by calcium channel blockers.

The direct tubular natriuretic effect of calcium channel blockers (CCBs) may be due to an interaction between CCBs and a renal tubular dopamine receptor. We therefore studied the effects of two chemically unrelated CCBs, diltiazem and isradipine, infused into the right renal artery of 5% saline-loaded anesthetized rats alone or in the presence of a D1 antagonist, SKF-83742. Isradipine (0.03 microgram.kg-1.min-1) or diltiazem (20 but not 10 micrograms.kg-1.min-1) alone produced an increase in urine flow and an approximate doubling of absolute and fractional sodium excretion, which was not seen in the left kidney or in the control animals (analysis of variance, Scheffé's test, P < 0.05). SKF-83742 alone given systemically or into the right renal artery did not affect these parameters but did block the actions of diltiazem or isradipine. There was no change in mean arterial pressure, renal blood flow, or glomerular filtration rate in any of the experiments. In additional studies, we found that a combined infusion of dopamine (0.1 microgram.kg-1.min-1) and diltiazem (10 micrograms.kg-1.min-1) (doses that by themselves did not alter renal function) produced a twofold or greater increase in urine flow and absolute and fractional sodium excretion; glomerular filtration rate was not significantly changed. Intrarenal arterial CCBs, without a change in renal hemodynamics, produce a natriuresis that is blocked by a D1 antagonist. Concomitant administration of diltiazem and dopamine (each in subeffective doses when used alone) produces a synergistic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Antinociceptive effects of intrathecal L-type calcium channel blockers on visceral and somatic stimuli in the rat.

UNLABELLED: L-type calcium channels can modulate neuronal transduction in the spinal cord. However, their role in noxious information processing in animals that are physiologically intact has not been elucidated. We evaluated the effects of L-type calcium channel blockers diltiazem and verapamil on somatic and visceral nociception at the level of the spinal cord. Intrathecal catheters were inserted at the L4-5 level in Sprague-Dawley rats. The tail flick (TF) test and colorectal distension (CD) test were used to assess somatic and visceral antinociceptive effects, respectively. Motor function was assessed by posture and muscle tone in the limbs. TF latency and CD threshold were measured before and for 180 min after the intrathecal administration of verapamil (50, 100, 300, and 500 microg), diltiazem (100, 300, 500, and 1000 microg), or isotonic sodium chloride solution. The percent maximal possible effect (%MPE) was calculated by transforming response threshold in TF and CD tests. Intrathecally administered diltiazem or verapamil increased both TF latency and CD threshold in a dose-dependent fashion. Isotonic sodium chloride solution, diltiazem 100 microg, and verapamil 50 microg did not increase %MPE in either test. Diltiazem 300 or 500 microg or verapamil 300 or 500 microg significantly (P < 0.05) increased %MPE, with the peak effects 5 min after administration and short-duration antinociception. %MPE was 100% until 15 min after the administration of diltiazem 1000 microg, and significant antinociception continued until 180 min in the TF test. Motor paralysis was observed after the administration of the larger dose of each drug. We demonstrated that intrathecally administered L-type calcium channel blockers diltiazem or verapamil produced both somatic and visceral antinociception and motor block dose-dependently. IMPLICATIONS: We examined the effects of intrathecally administered L-type calcium channel blockers diltiazem and verapamil on somatic and visceral nociception in rats. L-type calcium channel blockers produced antinociceptive effects, suggesting a possible clinical application to control pain.

Analgesics↗
PubMed2006

Calcium channel blockers for tocolysis: a review of their role and safety following reports of serious adverse events.

The use of nifedipine and other calcium channel blockers has become commonplace in the management of preterm labour. Several relatively small randomised trials have compared calcium channel blockers with beta-agonists and the meta-analyses of these studies have demonstrated superior or comparable efficacy and a superior adverse events profile. The safety of calcium channel blockers in pregnancy has not been rigorously evaluated and they remain unlicensed for use as tocolytics. Indeed, there is concern following a number of recent case studies that have reported serious adverse events after the administration of a calcium channel blocker as a tocolytic. In this article all these recently reported cases are critically reviewed and the pros and cons of tocolytic treatment options are discussed. Based on the findings of this review the following recommendations can be made with regard to tocolysis with calcium channel blockers: firstly, calcium channel blockers should not be combined with intravenous beta-agonists; secondly, intravenous nicardipine or high oral doses of nifedipine should not be used in cases where the mother is cardiovascular compromised or in cases of multiple gestation; finally, blood pressure should be monitored and cardiotocography recorded during the administration of immediate release tablets and patients should be advised to avoid chewing them. To truly establish the safety of tocolytics, all serious adverse effects of tocolytics should be reported to a central point and be critically reviewed.

Adrenergic beta-Agonists↗
PubMed1986

Calcium channel blockers in the management of hypertension in the elderly.

Calcium channel blockers seem to be particularly suitable for elderly hypertensive patients since these agents do not cause salt and fluid retention, postural hypotension, sedation, depression, or biochemical abnormalities. Moreover, their use is compatible with several common diseases of old age, such as diabetes, obstructive lung disease, and peripheral vascular disease. We recently conducted a study in 21 patients (average age, 79 +/- 2 years) who completed an eight-week trial with 20-mg nifedipine tablets taken twice daily. Mean blood pressure decreased from 191 +/- 2/96 +/- 2 mm Hg to 151 +/- 4/80 +/- 3 mm Hg. In 15 patients (71 percent), blood pressure decreased to less than or equal to 160/90 mm Hg; in four additional patients (19 percent), diastolic blood pressure decreased by 15 to 25 percent. Thus, there was a sustained lowering of blood pressure in 90 percent of the participants receiving nifedipine monotherapy. A review of recent studies in elderly hypertensive patients revealed similarly favorable results with calcium channel blockers given alone or in combination with other agents. The accumulating data suggest that these compounds may offer a useful new approach to the treatment of hypertension in old age. However, in these studies, the number of patients and the duration of follow-up need to be extended to confirm the favorable impression obtained thus far.

Aged↗
PubMed1995

Discriminative stimulus properties of isradipine: effect of other calcium channel blockers.

This study constitutes the first report of a calcium channel blocker used as a drug capable of controlling differential responding in a drug-discrimination paradigm. Male Sprague-Dawley rats were trained to discriminate between intraperitoneally administered 10.0 mg/kg isradipine and its vehicle in a two-lever, food-motivated, operant task. Once trained, rats displayed a dose-related decrease in discriminative responding when tested with lower isradipine doses. An analysis of the dose-response curve indicated an ED50 = 5.71 mg/kg. As all training and dose-response testing occurred at 60 min postadministration, experiments were conducted with varying injection-to-test intervals ranging from 15-240 min. Results indicate that the optimum time for discriminative performance was at the time used in training, and that discrimination returned to nondrug (vehicle) levels 2 h postinjection. Administration of other L-type calcium channel blockers, viz., nifedipine (5-50 mg/kg), diltiazem (10-60 mg/kg), or nicardipine (0.5-3.0 mg/kg), as well as a novel antipsychotic that inhibits dopamine release (10-30 mg/kg of CGS 10746B), did not produce isradipine-like discriminative effects. Thus, there was no generalization from the training dose of 10 mg/kg isradipine to any of these other agents, and the results are discussed in light of the possible specificity of the isradipine discriminative stimulus cue as it is produced in the central nervous system.

Animals↗
PubMed1999

Review of preclinical data of calcium channel blockers and atherosclerosis.

A variety of animal models have been used to determine whether calcium channel blockers exert an inhibitory effect on atherosclerotic lesion formation. These models include the cholesterol-fed rabbit, in which the lesions resemble the fatty-streak stage of atherosclerotic lesion development in humans. Diet-induced atherosclerosis in monkeys is also used and, in this case, the lesions resemble those found in humans, both in pathology and distribution. Other models involve mechanical injury superimposed on cholesterol feeding. Cellular and subcellular preparations are being used to investigate the mechanisms involved in the antiatherosclerotic activity of the calcium channel blockers. The ability of calcium channel blockers to slow atherosclerotic lesion formation is a class effect that is independent of their blood pressure-lowering effect, and occurs without any significant change in the plasma lipid profile. It is accompanied by a reduction in vessel wall cholesterol and calcium and is maintained over prolonged periods of treatment. The mechanisms that may be involved include inhibition of smooth muscle cell proliferation and migration, slowed platelet aggregation, restructuring of cholesterol-enriched cell membranes, enhanced gene expression for low-density lipoprotein receptor protein, inhibition of growth factor release, slowed calcium uptake, and restoration of endothelium-dependent relaxation.

Animals↗
PubMed1992

Selecting optimum antihypertensive therapy: indications for choosing a calcium channel blocker.

In choosing the optimum antihypertensive agent for an individual patient, various factors should be considered. Demographic characteristics (e.g., age, gender, race) and the circadian pattern of blood pressure elevation may influence the response to therapy. Concomitant therapy for coexisting medical disorders must be evaluated for possible drug interactions. Calcium channel blockers, which can be used in any age group, may be particularly useful in hypertensive patients with certain concurrent conditions (e.g., coronary artery disease, migraine, or gastrointestinal motility disorders). Life-style, including occupation and leisure-time activities, may contraindicate the use of certain drugs in a particular patient. It also may be necessary to consider the economic status of the patient, particularly in the elderly, who often have limited disposable income. Since to a great extent successful therapeutic management of hypertension depends on patient compliance, reduced frequency of dosing (i.e., once or twice daily) is desirable. The clustering of morbid events in the hours immediately following awakening highlights the need for therapy that provides 24-hour control, thereby ensuring adequate pharmacodynamic effects during that crucial period. The challenge is to select the most appropriate first-line agent (diuretic, beta blocker, calcium channel blocker, or angiotensin-converting enzyme inhibitor) for a particular patient.

Age Factors↗
PubMed1990

Cardiovascular and renal actions of endothelin: effects of calcium-channel blockers.

We have evaluated the effects of two calcium-channel blockers, verapamil (VP) and manganese (Mn), on endothelin (EN)-induced changes in systemic and renal function in pentobarbital sodium-anesthetized female rats and male and female dogs. In the rat studies, saline was infused at 24 microliters/min iv with or without (n = 10) two doses of VP (0.02 mg.kg-1.min-1, n = 5; 0.03 mg.kg-1.min-1, n = 3) or Mn (0.5 mg.kg-1.min-1, n = 5) throughout the entire experiment. After surgery, rats were allowed 60 min to stabilize, and three 20-min control clearances were collected. EN (100 ng.kg-1.min-1) was then added to the infusate for 30 min. EN alone caused an increase in mean arterial pressure (MAP) and a decrease in the glomerular filtration rate (GFR). VP at either dose and Mn totally blocked the EN-induced increase in MAP. However, the two calcium-channel blockers had no effect on the renal action of EN; the GFR (in ml/min) decreased (at 30 min of EN infusion) from 2.7 +/- 0.1 (SE) to 0.7 +/- 0.1 (P less than 0.01) in controls, from 2.5 +/- 0.3 to 0.4 +/- 0.3 with the lower dose of VP (P less than 0.01), from 2.3 +/- 0.1 to 0.6 +/- 0.2 with the higher dose of VP (P less than 0.01), and from 1.5 +/- 0.5 to 0.9 +/- 0.6 with Mn (P less than 0.05). Infusion of EN alone (10 ng.kg-1.min-1, n = 5) and EN with VP (50 micrograms/min, n = 3) into the renal artery of dogs reduced renal blood flow from 3.5 +/- 0.4 to 0.9 +/- 0.2 and from 3.6 +/- 0.6 to 1.2 +/- 0.6 ml.g-1.min-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗